Examples of key questions are: what are the mechanisms leading different gene mutations (e.g., C9orf72 and GRN) to cause the same neuropathological lesion (TDP-43 inclusions), though with a different clinical manifestation (ALS and/or FTD for C9orf72, purely FTD for GRN); and can we extend mechanisms uncovered using models of a specific familial form of the disease (i.e., ALS-SOD1) to other genetic forms and sporadic cases? The gene discussed is GRN; the disease is amyotrophic lateral sclerosis.